Imbalance of proresolving lipid mediators in persistent allodynia dissociated from signs of clinical arthritis

Abstract

Rheumatoid arthritis-associated pain is poorly managed, often persisting when joint inflammation is pharmacologically controlled. Comparably, in the mouse K/BxN serum-transfer model of inflammatory arthritis, hind paw nociceptive hypersensitivity occurs with ankle joint swelling (5 days after immunisation) persisting after swelling has resolved (25 days after immunisation). In this study, lipid mediator (LM) profiling of lumbar dorsal root ganglia (DRG), the site of sensory neuron cell bodies innervating the ankle joints, 5 days and 25 days after serum transfer demonstrated a shift in specialised proresolving LM profiles. Persistent nociception without joint swelling was associated with low concentrations of the specialised proresolving LM Maresin 1 (MaR1) and high macrophage numbers in DRG. MaR1 application to cultured DRG neurons inhibited both capsaicin-induced increase of intracellular calcium ions and release of calcitonin gene-related peptide in a dose-dependent manner. Furthermore, in peritoneal macrophages challenged with lipopolysaccharide, MaR1 reduced proinflammatory cytokine expression. Systemic MaR1 administration caused sustained reversal of nociceptive hypersensitivity and reduced inflammatory macrophage numbers in DRG. Unlike gabapentin, which was used as positive control, systemic MaR1 did not display acute antihyperalgesic action. Therefore, these data suggest that MaR1 effects observed after K/BxN serum transfer relate to modulation of macrophage recruitment, more likely than to direct actions on sensory neurons. Our study highlights that, in DRG, aberrant proresolution mechanisms play a key role in arthritis joint pain dissociated from joint swelling, opening novel approaches for rheumatoid arthritis pain treatment.

Harnessing Inflammation Resolution in Arthritis: Current Understanding of Specialized Pro-resolving Lipid Mediators’ Contribution to Arthritis Physiopathology and Future Perspectives

“…MaR1, on the other hand, upon a single treatment, displays 5 days of analgesic effect when treatment is performed before stimulus with CFA and 3 days of analgesia when treatment is performed 24 h after the stimulus ( Fattori et al, 2019 ). In corroboration to our study, Allen and colleagues demonstrated that MaR1 presents 14 days of analgesia after repeated treatments ( Allen et al, 2020 ). These sets of data show that isolated SPMs demonstrate time-dependent and long-term efficacy even upon single treatment, which might be useful for the treatment of inflammatory diseases.…”

“…By this neuronal regulation, intrathecal treatment with MaR1 reduces the peripheral recruitment of inflammatory neutrophils and macrophages, reducing in addition to pain, peripheral inflammation (Fattori et al, 2019). In corroboration, Allen et al (2020) demonstrated that MaR1 also reduces calcium influx induced by capsaicin (TRPV1 agonist) in a GPCR-dependent manner and CGRP release. In another study, CIA-associate clinical score and cytokine profile were abrogated with MaR1 treatment (Jin et al, 2018).…”

“…Despite the completion of the clinical studies, up to this point, no final results were published. Focusing on pain, a major symptom in rheumatic conditions, evidence have shown that SPMs can block nociceptor activation, hence decreasing pain (revised, Fattori et al, 2019Fattori et al, , 2020Allen et al, 2020).…”

“…In the resolution phase, the lipid class switch supports the inflammation resolution and restore the levels of SPMs ( Arnardottir et al, 2016 ). While the joint has the health status restored, in the DRG, the class switch does not occur at the same pace, and the imbalance between pro-inflammatory mediators and SPMs in the dorsal root ganglia (DRG) result in persistent pain ( Allen et al, 2020 ).…”

Neuromodulation, Specialized Proresolving Mediators, and Resolution of Pain

“…In a mouse model of rheumatoid arthritis, persistent pain was not associated with joint swelling, but instead, was associated with decreased concentrations of MaR1. Furthermore, systemic MaR1 administration caused sustained reversal of mechanical hypersensitivity and reduced inflammatory macrophage numbers in DRG [78]. Given that macrophages are critical contributors to chronic pain pathogenesis by forming bidirectional communication with nociceptors [79], it remains important to identify whether endogenous macrophagederived maresins contribute to chronic pain resolution.…”